This invention relates to methods for administration of taxane/tocopherol formulations for the treatment of cancer.
Paclitaxel is one of the most potent anticancer agents for the treatment of several cancers, including breast, ovarian, and lung cancers. Paclitaxel is a lipophilic molecule and is virtually insoluble in water. The poor aqueous solubility of paclitaxel has hindered the development of a suitable formulation for administration to patients.
The commercially available paclitaxel product, TAXOL (Bristol-Myers Squibb Oncology), is formulated in a vehicle containing an approximately 1:1 (v/v) mixture of polyoxyethylated castor oil (Cremophor EL) and ethanol. There are several disadvantages associated with the use of the TAXOL formulation of paclitaxel. Foremost among these is the presence of Cremophor EL in the formulation. Cremophor EL has been associated with bronchospasm, hypotension, and other manifestations of hypersensitivity, particular following rapid administration. As a result, the administration of TAXOL requires long infusion times of diluted material and premedication to reduce these adverse effects (Suffness, M. (1995), TAXOL Science and Applications, CRC Press). Typically, TAXOL is diluted about 10 to 20 fold prior to administration, and the approved infusion times range from 3 to 24 hours.
Several attempts have been made to provide paclitaxel formulations that overcome the problems associated with TAXOL. In one approach, the aqueous solubility of paclitaxel has been enhanced through the development of pro-drugs, such as pegylated paclitaxel or polyglutamate paclitaxel. These compounds successfully increase the aqueous solubility of paclitaxel and thereby avoid the use of toxic solvents to solubilize paclitaxel. However, the pro-drugs require the presence of enzymes in the blood or tissue to cleave the water-soluble component of the pro-drug from the paclitaxel moiety. Therefore, the therapeutic utility of paclitaxel can be compromised if the level of activity of the enzyme required to release the paclitaxel from the pro-drug is low, as is frequently the case among the cancer patients. Generally, these pro-drugs are infused slowly to avoid adverse reactions.
Another approach has used human albumin coated paclitaxel nanoparticles to avoid the use of toxic solvents. However, the utility of these nanoparticles is limited by the slow dissociation of paclitaxel from the albumin coat.
Therefore, there remains a need in the art for paclitaxel formulations that overcome the disadvantages of prior art formulations. Moreover, there remains a need to identify a method for administrating paclitaxel that will reduce side effects and improve the therapeutic efficacy of paclitaxel.
The present invention provides methods for administration of taxane formulations.
In one aspect, the invention provides methods for administering taxanes without dilution and mixing of the taxane formulation with other excipients or carriers prior to administration. In some embodiments, the invention provides methods for administering a taxane as a bolus injection. In some embodiments, the invention provides methods for administering a taxane as an intravenous infusion in less than about 30 minutes. In some embodiments, the invention provides methods for administering a taxane using only antihistamine premedication.
In another aspect, the invention provides methods for administering taxanes to deliver high concentrations of paclitaxel in blood. In some embodiments, the invention provides methods for administering taxanes to deliver mean peak blood concentrations of taxanes of greater than about 4,000 ng/mL after administration of a taxane dose of 175 mg/m2. Some embodiments provide methods for administration that provide a mean extrapolated area-under-the-curve (AUC) concentration of taxanes in blood of greater than about 16,000 ng*h/mL after administration of a taxane dose of 175 mg/m2. In some embodiments, the methods of the invention result in a mean total body clearance of the taxanes of less than about 11 L/h/m2.
In another aspect, the invention provides methods for administering taxanes to deliver high concentrations of taxanes in tumors. In some embodiments, the invention provides methods for administering taxanes to provide a mean peak taxane concentration in tumors of more than 6000 ng/g of tumor mass after administration of a taxane dose of 10 mg/kg. In further embodiments, the invention provides methods for administering taxanes to provide a mean area-under-the-curve (AUC)0xe2x86x92t concentration of taxanes in tumors of more than 80 xcexcg*h/g of tumor mass after administration of a dose of 10 mg/kg.
In another aspect, the invention provides methods for administering taxanes to obtain increased anti-tumor activities compared to TAXOL. In some embodiments, the invention provides methods for administering taxanes that are effective against taxane-resistant tumors.
In another aspect, the invention provides methods for treating subjects suffering from tumors. In some embodiments, the invention provides methods for treating subjects suffering from colorectal adenocarcinoma. In some embodiments, the invention provides methods for treating subjects suffering from carcinomas such as breast carcinoma, lung carcinoma, skin carcinoma, gastrointestinal carcinoma, ovarian carcinoma, and uterine carcinoma.